Ethanol modulate central and peripheral immune responses via HMGB1, IL-1Beta, and other Immune Signaling Molecules

乙醇通过 HMGB1、IL-1Beta 和其他免疫信号分子调节中枢和外周免疫反应

• 批准号: 10238811
• 负责人: Leon Garland Coleman
• 金额: $ 12.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238811
• 关键词: Accounting; Acute; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholism; Alcohols; Autophagocytosis; Basic Science; Biological Assay; Body Surface; Brain; Burn injury; Cell Communication; Cell Culture System; Cells; Cessation of life; Chronic; Clinical; Clinical Research; Co-Immunoprecipitations; Companions; Critical Illness; Data; Development; Disease; Doctor of Philosophy; Dose; Ensure; Enzymes; Ethanol; FRAP1 gene; Flow Cytometry; Foundations; Glycyrrhizic Acid; Goals; HMGB1 gene; Hour; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response Pathway; Injections; Innate Immune Response; Innate Immune System; Interleukin-1; Interleukin-1 beta; Intestinal permeability; Kineret; Label; Laboratories; Lead; Learning; Link; Lipids; Liver; Lung; Mass Spectrum Analysis; Measures; Mediating; Mentors; Mentorship; Microglia; Modeling; Mus; Natural Immunity; Neuroglia; Neurons; Organ; Outcome; PTEN gene; Pathology; Pathway interactions; Patients; Peripheral; Pharmacotherapy; Plasma; Pneumonia; Poly I-C; Proteins; Recording of previous events; Recovery; Research; Research Personnel; Role; Secondary to; Sepsis; Severity of illness; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; Slice; Spleen; Stomach; TLR3 gene; TLR4 gene; Techniques; Testing; Time; Tissues; Viral; Western Blotting; Work; alcohol effect; alcohol exposure; alcohol use disorder; career; career development; cell type; cytokine; experimental study; fluorescence imaging; immune activation; immunocytochemistry; in vivo; inhibitor/antagonist; laboratory experience; mortality; neuroinflammation; novel; novel therapeutics; preventable death; problem drinker; protective effect; research and development; response; systemic inflammatory response; translational scientist; uptake; vesicular release; wortmannin

Project Summary/Abstract Alcohol use disorders are third leading cause of preventable death, accounting for approximately 90,000 preventable deaths each year (Danaei et al 2009). Nearly 50% deaths are secondary to diseases that are associated with inflammation and aberrant immune activation such as sepsis and alcoholic liver disease (Mokdad et al 2000). Recent discoveries find that alcohol activates the innate immune system in both the CNS and periphery. Thus, understanding the effects of alcohol on the immune system is critical to form a foundation of discovery leading to the understanding of both the pathology of alcoholism and numerous alcohol-associated diseases. We have found recently that alcohol activates the innate immune system through the ‘master regulator’ of innate immunity, HMGB1. In this proposal we aim to investigate the effects of alcohol on central and peripheral immune activation through HMGB1 and its companion cytokine IL-. Using in vitro cell culture systems (Aim 1), in vivo experiments (Aim 2-3) and assessments in human alcoholics, burn patients and alcoholic hepatitis patients (Aim 4), we hope to gain an understanding of the immune effects of alcohol throughout the body. I will gain new laboratory experience with real time-PCR, enzyme-linked immunosorbant assays, co-immunoprecipitation, western blotting, intracerebral AAV5 viral injections, mass spectrometry, immunocytochemistry, and live fluorescent imaging. We also investigate a novel mechanism of cell-cell communication in this pathology, alcohol-induced release of pro-inflammatory microparticles. Further, we investigate the role of the PTEN/PI3K/Akt/mTOR pathway in the immune effects of alcohol, and study inhibitors of this pathway which may be novel therapeutic options. Our preliminary data strongly suggest that alcohol causes central and peripheral HMGB1 and IL-1 release in microparticles through a PTEN/PI3K/Akt/mTOR linked mechanism. This project also incorporates substantial career development with career and research mentoring from top tier researchers and clinicians, the learning of new experimental techniques, and course work to enhance clinical/translational expertise. Co-mentors Fulton T. Crews, PhD and Bruce Cairns MD provide a depth of basic science, clinical research, and career development mentorship that will help ensure the successful transition of the candidate to being a top independent translational researcher.

项目摘要/摘要 饮酒障碍是可预防死亡的第三主要原因 每年约有90,000例可预防的死亡（Danaei等，2009）。近50％ 死亡是与感染和异常相关的疾病继发的 免疫激活，例如败血症和酒精性肝病（Mokdad等，2000）。 最近发现，酒精激活了同时的先天免疫系统 中枢神经系统和外围。这是了解酒精对免疫系统的影响 构成发现的基础至关重要 酒精中毒的病理和许多与酒精相关的疾病。我们找到了 最近，酒精通过“主调节器”激活先天免疫系统 先天免疫，HMGB1。在此提案中，我们旨在调查酒精的影响 通过HMGB1及其伴侣在中央和周围免疫激活上 细胞因子IL-。使用体外细胞培养系统（AIM 1），体内实验（AIM 2-3） 以及人类酗酒者，烧伤患者和酒精性肝炎患者的评估 （AIM 4），我们希望能够了解整个酒精的免疫作用 身体。我将通过实时PCR，酶联的新实验室经验 免疫吸附测定，共免疫沉淀，蛋白质印迹，脑内AAV5 病毒注射，质谱，免疫细胞化学和活荧光成像。 我们还研究了这种病理学中细胞 - 细胞通信的新机制， 酒精诱导的促炎性微粒的释放。此外，我们研究了 pten/pi3k/akt/mtor途径在酒精的免疫学影响中的作用，并研究 这种途径的抑制剂可能是新的治疗选择。我们的初步数据 强烈建议酒精会导致中央和周围HMGB1和IL-1释放 通过PTEN/PI3K/AKT/MTOR链接机制在微粒中。这个项目也是如此 将实质性的职业发展与职业和研究的心理联系在一起 顶级研究人员和临床医生，新实验技术的学习以及 课程工作以增强临床/翻译专业知识。联合官员Fulton T. Crews， 博士和布鲁斯·凯恩斯（Bruce Cairns）医学博士提供了基础科学，临床研究和 职业发展指导将有助于确保成功过渡 候选人是一名最高独立的翻译研究人员。

项目成果

Chronic Ethanol Causes Persistent Increases in Alzheimer's Tau Pathology in Female 3xTg-AD Mice: A Potential Role for Lysosomal Impairment.

• DOI: 10.3389/fnbeh.2022.886634
• 发表时间: 2022
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3

Microglial depletion and repopulation: a new era of regenerative medicine?

• DOI: 10.4103/1673-5374.300439
• 发表时间: 2021-06
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Barnett AM;Crews FT;Coleman LG
• 通讯作者: Coleman LG

Ethanol Induces Secretion of Proinflammatory Extracellular Vesicles That Inhibit Adult Hippocampal Neurogenesis Through G9a/GLP-Epigenetic Signaling.

• DOI: 10.3389/fimmu.2022.866073
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Adolescent Binge Alcohol Enhances Early Alzheimer's Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation.

• DOI: 10.3389/fphar.2022.884170
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Barnett, Alexandra;David, Emeraghi;Rohlman, Aaron;Nikolova, Viktoriya D.;Moy, Sheryl S.;Vetreno, Ryan P.;Coleman, Leon G., Jr.
• 通讯作者: Coleman, Leon G., Jr.

Extracellular microvesicles promote microglia-mediated pro-inflammatory responses to ethanol.

• DOI: 10.1002/jnr.24813
• 发表时间: 2021-08
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Crews FT;Zou J;Coleman LG Jr
• 通讯作者: Coleman LG Jr